Leveraging Medulloblastoma Clonal Dynamics to Overcome Treatment Resistance

Medulloblastoma (MB) is a common pediatric brain tumor with distinct molecular subgroups, of which, Group 3 MB is associated with increased recurrence, metastatic potential and poor patient outcomes. Small molecule inhibitors targeting BMI1 have been shown to be efficacious against several types of malignant tumors, including pediatric MB. While our previously published in vivo study provides a promising proof-of-concept for the therapeutic targeting of BMI1 in Group 3 MB with small molecule inhibitor, it is not sufficient to eradicate the tumour. Overall design: In this study, following preclinical validation of BMI1 inhibitor PTC596, DNA barcoding technology was leveraged to profile in vivo clonal dynamics of Group 3 MB in response to the established chemoradiotherapy regimen alone and in combination with PTC596. Following demonstration of a small number of treatment-refractory clones we sought to identify potential druggable molecular vulnerabilities by utilizing phosphoproteomic profiling and genome-wide CRISPR screening. *************************************************************** The table below lists GEO accessions reused/reanalyzed for this study. ***************************************************************